THE GLOBAL RESOURCE FOR ANTI-AGING

Anti-Aging
-Aging
A nti - A gi ng MEDI CA L N EW S W I N T ER 2 0 1 0

M E D I CA L N E W S

ESTROGEN
METABOLISM
ITS RISK ON BREAST CANCER
AND MITIGATING EFFECTS

TELOMERES &
TELOMERASE
AS NATURAL THERAPEUTIC
TARGETS
•

IN THIS ISSUE
Welcome Letter PG 5
OFF IC I AL S HOW HA N D BO OK

Immune Enhancement
By Nature PG 10
Nutritional and Genetic
Strategies for longevity PG 37
Exhibitor Listings PG 190
Product Announcements PG 190

SPECIAL GUEST: Fish Oil vs. Krill Oil PG 208

Suzanne Somers

18TH ANNUAL WORLD CONGRESS

ON ANTI-AGING MEDICINE AND BIOMEDICAL TECHNOLOGIES
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Abstract
A
genomic understanding of
aging is paving the way to iden-
tify interventions that can have
significant impact on the aging process.
The polymorphic nature of aging indi-
cates that any anti-aging strategy has
to start with a better understanding of
genes that affect tissue viability.
Our anti-aging approach has always
centered on the foundation of good
macro and micro-nutrition, including
the consumption of plentiful plant-
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based antioxidants and phytonutrients.
However recent advances, especially
with the mapping of the human genome
and the subsequent development of
DNA microarrays provide (a) an op-
portunity to explore the mechanisms of
aging and (b) the tools to begin address-
ing aging at its most fundamental level.
We believe that if we are to widen the
gap between chronological and biologi-
cal age we must better understand the
role of gene expression in aging and how
dietary ingredients interact with gene
expression in a positive way.
ANTI-AGING MEDICAL NEWS [37
Introduction
Aging is not an episodic process;
rather, it is the consequence of a con-
tinuum of cumulative damage occur-
ring at the molecular, cellular and tissue
levels. The rate of aging rests on factors,
internal and external, that can either
positively or negatively influence the
balance between tissue preservation or
repair, and damage. Attenuation of ag-
ing is entirely dependent on mitigating
such molecular damage by augmenting
protection and compensatory repair
mechanisms or slowing the degen-
erative processes. In a practical sense
we’ve all probably witnessed clear
discrepancies between chronological
and biological age in certain individu-
als. And while it has been proposed
that genetic factors contribute to the
phenomenon of people looking old,
or young, for their years, most of us
intuitively suspect that there are some
environmental components over which
we wield a certain amount of control.
Therefore, if we are to widen the gap
between chronological and biological
age, we must understand the various
mechanisms involved in aging and
devise effective strategies that turn
these mechanisms in favor of tissue
protection or repair and regeneration.
The question we are asking is: what
FIGURE 1: LGT identified biomarkers of age across
seven strains of mice (5 months vs. 28-30 months
old) so that only the most conserved relevant
patterns of age-related gene expression markers
were considered. RTqPCR was used to confirm a
panel of 10-20 genes in each tissue.
38 [ANTI-AGING MEDICAL NEWS
are the lifestyle factors and nutritional
components that may assist us in taking
control of our own aging process so
that we can age healthily and reduce
age-related morbidity?
Macro and Micro Nutrition
A major factor in healthy aging
involves what, and how much, we eat.
There is ample evidence that poor nu-
trition, which includes overeating and
poor nutrient density, is linked with an
increased risk for many degenerative
diseases including heart disease, diabe-
tes and cancer. It is now also becoming
clear that even marginal micronutrient
deficiencies over time lead to acceler-
ated aging.1 Deficiencies in several
different micronutrients including
folic acid, vitamin D and Magnesium
lead to DNA damage and accelerate
age-related mitochondrial dysfunction;
which in turn leads to further oxidative
damage to DNA, RNA, proteins and
membrane lipids leading to functional
decline in mitochondria, cells, tissues
and organs. Since multiple studies and
extensive government-commissioned
surveys point to the widespread nature
of inadequate dietary intakes of fruits
and vegetables (and therefore vitamins
and minerals)2 it seems prudent that all
individuals either improve their diets or
supplement their diets with a multi-
vitamin mineral supplement to ensure
that there are no shortfalls in essential
nutrients.
Free-radical Biology and Antioxidants
A leading hypothesis of aging is based
on the free radical theory of aging by
Harman3 who argued that oxygen-
free radicals produced during normal
cellular respiration cause cumulative
damage to molecules which progres-
sively leads to loss of functionality of
the organism. Since Harman’s theo-
ries were first proposed, a huge body
of literature has emerged providing
evidence that free radicals and oxida-
tive stress are involved in many disease
states, especially age-related degenera-
tive disease. Although oxidative stress
may be a significant factor associated
with aging, it is clearly not the only
contributor and recently evidence is
emerging to support the concept that
vitamins, minerals, and phytonutrients
not only fight free radicals, but they
exert perhaps even more powerful anti-
aging effects through a non-antioxidant
role. Phytonutrients, many of which
are antioxidants, also influence the ex-
pression or activity of factors involved
in aging including, for example, sirtuins,
AMPK, NFKB and PGC-1 alpha to
name a few.4-6 Thus it is becoming in-
creasingly clear that the phytonutrients
we thought were merely antioxidants
are also capable of modulating gene
expression.
Gene Expression Science
It is clear that a nutraceutical ap-
proach to anti-aging must take into ac-
count the polymorphic nature of aging,
and that the crosstalk among multiple
genes plays a more important role than
the action of a single gene in mediat-
ing the survival of an organism. Since
the development of DNA microarrays
that allow scientists to measure the
work output of all of the genes in a
single experiment, it is now possible to
rapidly explore the differences in the
expression of multiple genes between
two or more biological conditions in
a single experiment. Our research
and development team at Nu Skin
became intrigued with the possibility
of measuring the aging process objec-
tively at the genetic expression level
after reading some of the exceptional
work published by Weindruch, Prolla
and colleagues (LifeGen Technologies,
LLC) (LGT) wherein a powerful tech-
nique of differential expression analysis
was being used to conduct genome-
wide searches for consistent changes
in gene expression patterns that occur
during the aging process.7, 8
Studies using whole-genome tran-
scriptional profiling typically identify
thousands of genes that are changed
in expression with age. Since many of
these age-related changes are not univer-
sal, but rather are specific to the genetic
background of the organism being stud-
ied, LGT identified biomarkers of age
across seven strains of mice (5 months
vs. 28-30 months old) so that only the
most conserved relevant patterns of age-
related gene expression markers were
considered. Moreover, these analyses
were performed in three tissues (heart,
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cerebral cortex and gastrocnemius) and
real-time quantitative PCR was used
to confirm a panel of 10-20 genes in
each tissue. Data generated from such a
model are not only of a higher standard
of rigor, but they are more likely to
be applicable to human aging as well.
Using this approach statistically robust
patterns, or signatures, of youthful and
older gene expression have emerged
which enabled us to essentially measure
aging at the genetic level. The possibil-
ity now existed to screen for ingredients
or formulations for their ability to retard
the aging process. This is the procedure
that Pharmanex has adopted in collabo-
ration with LGT to target aging at the
source, gene expression, in an approach
that we call ageLOC science.

Microarrays, Databases and

Bioinformatics as a Guide to Product
Development
In our first screening experiment
certain ingredients emerged for their
abilities to reset gene expression to
that of a more youthful pattern. A
particular preparation of pomegranate,
for example, was the most effective
compound tested, opposing 32-65% of
the overall aging change depending on
the tissue studied. Other ingredients
and formulations also emerged as hav-
ing potent effects on gene expression
that attenuated age-associated patterns
of expression. The results of our first
round of screening provided an impor-
tant insight into ingredients that influ-
ence gene expression in a positive way
and served as an important foundation
to further product development.
In addition to helping identify
individual gene expression signatures
associated with aging, DNA microar-
ray technology in conjunction with
gene databases and bioinformatics can
also be used to identify the expression
levels of groups of genes that work
together to serve a particular meta-
bolic pathway. We added the use of
such pathway analyses to our reper-
toire of microarray-related gene tools
to help further guide our product
development in formulating anti-aging
products by applying it to the concept
of age-related vitality loss. One of the
earliest manifestations of human aging
is a decline in vitality. Mitochondrial
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FIGURE 2: This heat map illustrates gene expression of three groups from a pre-clinical test with one of
the ageLOC Vitality ingredients: young (column 1), old (column 2), and old with ageLOC science (col-
umn 3). Each row represents one of 52 genes comprising the mitochondrial Youth Gene Cluster (mtYGC).
Columns 1 and 2 show that each of the 52 genes became more or less active during the aging process.
In column 3, the YGC activity pattern of the old with ageLOC science group has been reset to a gene
expression pattern similar to the young group in column 1.
dysfunction associated with aging tion, Cs-4 opposed the effects of aging
yields bioenergetic defects within the in several gene ontology pathways.
cell9 that exert profound effects on In essence we were able to identify
physical and mental vitality. Our goal mitochondrial-related nuclear encoded
was to identify and target functional genes which changed consistently in
gene clusters associated with mito- expression with age, or mitochondrial
chondrial aging. youth gene clusters (YGC). A number
In our attempt to identify these gene of natural compounds were screened
pathways we found that of 20,687 for their ability to reset the expression
gene transcripts measured by the Af- profile of these genes to a more youth-
fymetrix Mouse Genome array, 1241 ful level. One ingredient, Cordyceps
were associated with the mitochondria sinensis Cs-4 (Cs-4)10 was shown to
by pathway ontology (using a gene markedly attenuate these age-related
ontology database). After our murine gene expression changes in the mito-
feeding studies and microarray screen- chondria, suggesting its potential use
ing we found that 172 of these genes as a therapeutic intervention of age re-
changed in expression during aging in lated vitality loss. Ongoing studies are
cerebral cortex tissue. In gastrocnemius utilizing this technique to investigate
tissue 220 genes changed which age. the effects of a variety of natural ingre-
Cs-4 opposed the age-related changes dients in brain, muscle and other tis-
in 52 of these genes (P<0.05). In addi- sues, but the sum of such explorations
ANTI-AGING MEDICAL NEWS [39
 Anti-aging Science:
where we were:
FIGURE 3: Mainstream anti-aging approaches for years have centered on the foundation of good
macro and micro-nutrition and antioxidants. However it is becoming increasingly clear that some of the
phytonutrients we thought were merely antioxidants are also capable of modulating gene expression
and play a role in aging.
so far, into the ability of certain natural
products to influence gene expression
in a positive way, has provided strong
guidance to our product development
process targeted at attenuation of the
aging process.
Functional Studies
The techniques that we have used
for studying gene expression have not
disappointed us in their promise as tools
explore the mechanisms of aging and
drive us towards meaningful product
development strategies. We see great
promise in the ability of certain nutra-
ceutical ingredients and formulations to
have a marked effect on gene expres-
sion to oppose age-related changes. The
next logical step is to support these gene
expression data with functional studies.
Indeed, the ingredients that we selected
for gene expression screening were
based on promising functional studies
that had already been performed. How-
ever, to close the circle, we have fol-
lowed up these promising gene expres-
sion data with further functional, safety
and efficacy studies in both animals
and humans. Some of these studies are
already completed and have provided
positive correlation and confirmation of
the gene expression data; other studies
are still underway.
Conclusion
Since aging can be considered as
a function of how genes respond to
40 [ANTI-AGING MEDICAL NEWS
Anti-aging Science Now
diet and environmental perturba-
tions through gene expression while
maintaining their primary function
to survive, we chose to exploit a gene
expression approach to screen several
nutraceutical ingredients and formula-
tions for their effects on retarding the
aging process. We called this approach
ageLOC science. Our first foray into
this approach involved targeting age-
related vitality loss through an explo-
ration of the gene expression changes
involved in mitochondrial aging. We
identified tissue-specific functional
YGCs, or signatures of gene expression
changes associated with mitochondrial
aging and screened for ingredients
that restored the more youthful pat-
tern of gene expression. Functional
studies have confirmed the promise
offered by the gene expression study
results. It is our opinion that while
a foundation sound of nutrition and
a positive lifestyle are key to healthy
aging and compression of morbidity,
there is much to be gleaned from an
understanding of gene expression as
it relates to the aging process as we
pursue the goal dying young - as late
in life as possible. ‹
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◗ Dr. Bartlett has degrees in Biochemistry and Or-
ganic Chemistry from the Australian National Uni-
versity and a Ph.D. in Immunology and Cell Biology
from the John Curtin School of Medical Research
in Canberra, Australia. In Australia he conducted
research on cardiovascular disease with an em-
phasis on the role of reactive oxygen species and
free radicals. He also studied the role of blood
platelets in heart disease, and helped publish the
first scientific report of a biochemical link between
cigarette smoking and atherosclerosis.
Later Dr. Bartlett became interested in autoim-
mune inflammatory diseases and examined a
number of plant-derived substances for their abil-
ity to inhibit graft rejection, inhibit cancer metas-
tasis – or spreading – as well as natural products
that were able to inhibit autoimmune disease.
Before joining Pharmanex Dr. Bartlett was a visiting
scientist at the National Institutes of Health, Na-
tional Cancer Institute in Bethesda, MD where, at
the National Cancer Institute, he investigated the
interaction of T-cells with the blood vessel wall, and
the role of various adhesion molecules that are
used by these cells to communicate with one an-
other. He is currently the Vice President of Global
Research and Development for Pharmanex.
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